Containers for pharmaceuticals, particularly for use in radioisotope generators

ABSTRACT

The invention is directed to improved containers for pharmaceuticals and any tubing and tubing connectors associated therewith, particularly containers for pharmaceuticals which are irradiated, heated or otherwise subjected to increased pressure. In a preferred embodiment, the invention is directed to an improved container for use in a radioisotope generator, such as a rubidium-82 generator.

This is a divisional application of U.S. application Ser. No.10/597,456, filed Jan. 17, 2007, now allowed, which claims priority fromPCT Application No. PCT/US2005/030796, filed Aug. 30, 2005, which claimspriority from provisional U.S. Application No. 60/605,481, filed Aug.30, 2004.

TECHNICAL FIELD OF THE INVENTION

The invention is directed to improved containers for pharmaceuticals andthe tubing and tubing connectors associated therewith, particularlycontainers for pharmaceuticals which are heated, irradiated or otherwisesubjected to increased pressure. In a preferred embodiment, theinvention is directed to an improved container for use in a radioisotopegenerator. Specifically, the designs and materials of the columncontainer and its closure and associated tubing and tubing connectorshave been improved.

SUMMARY OF THE INVENTION

The invention includes improved pharmaceutical containers, particularlyimproved containers for pharmaceuticals that are subjected to increasedpressure (such as by heating or other means) and/or are subjected toradioactivity. In a preferred embodiment, the invention is directed toan improved container, also called a column, for use in a radioisotopegenerator. In an especially preferred embodiment, the improved column isfor use with rubidium-82 generator such as those disclosed in U.S. Pat.Nos. 3,953,567; 4,400,358; 4,406,877; 4,562,829; 4,585,009; 4,585,941;and 5,497,951, incorporated herein by reference in their entirety. In aparticularly preferred embodiment, the improved column is used in arubidium-82 generator such as that sold under the trade name CardioGen®.

The improved pharmaceutical container of the invention includes animproved seal and crimping process, as well as changes to the design ofthe stopper and the container to prevent blockages and improveconsistency in packing and closing the container, which improves flowrate and elution from the column.

Further improvements include constructing the container and stopper outof radiation resistant or tolerant materials. In addition, flexibletubing used with the container is made of a radiation resistant ortolerant material, and the Luer locks used to fasten the flexible tubingto the container is made of a radiation resistant or tolerant materialand is further improved to insure a tight, secure lock which will notinadvertently loosen or disconnect.

Specifically, the improved container has a new, stronger seal which isused to crimp the stopper in a pharmaceutical container andparticularly, which is used to seal a radioisotope generatorcolumn/stopper assembly system, such as the CardioGen® system. Thisimproved seal prevents leakage, even at increased pressure, and reducesballooning of the rubber stopper material. The seal has a configurationsimilar to one of those shown in FIG. 5B through FIG. 5F and FIGS. 6Aand 6B and is made of any suitably strong material including metal orplastic. A pneumatically operated automatic or semi-automatic crimper,set at optimized pressure, is preferably used to crimp the seal duringassembly of a pharmaceutical container such as a radioisotope generatorcolumn/stopper assembly system. The invention includes identification ofoptimized crimping pressure(s) for crimping the seal (regardless ofmaterial) to a pharmaceutical container such as a glass or plastic vialor column and thus securing in place a rubber closure(s) when using anautomatic crimping system and/or manual crimping.

The stopper which is crimped into place is also improved. Specifically,it is made of a material which is radiation resistant or tolerant, isresistant to ballooning and can withstand the pressure at which thecontainer operates. Additionally, the configuration and placement of thestopper at the bottom of the column reduces the “dead volume”-spacewhere non-radioactive, decayed eluate could mix with (and dilute) fresh,radioactive eluate, reducing the efficacy of the eluent.

The improved pharmaceutical container also includes improvements to thedesign which improve its packing/assembly and thus ensure specified flowof eluent through the container.

These improvements are illustrated in the context of a radioisotopegenerator column container. Flow rate of the eluent through the columncould be partially or completely blocked if the stopper blocks theoutlet arm of the column. As shown in FIGS. 1A-1G, the outlet arm of thecontainer of the invention has been repositioned slightly and a smallpiece of plastic removed from the inside edge of the column to create arecess or notch where the outlet arm enters the column lumen to preventa stopper from blocking flow. See FIG. 4. A small reinforcement piece ofresin is added to the outside of the column between the outlet arm andcolumn body to provide additional strength.

Another improvement in the containers of the invention addressesconsistency of assembly and packing of the containers. In prior columnsfor a radioisotope generator, a plastic basket or spacer was suppliedseparately and was placed on the top of the column packing before theseal was inserted and the seal crimped into place. In these priorcolumns, placement of the baskets or spacers, which hold the columnpacking in place, could vary significantly, potentially creating someproblems with consistency in packing. In the improved columns, two smallorientation knobs have been added to the outside of the topbasket/spacer and the orientation knobs are positioned 180° apart. Theseknobs fit into two small slots cut into the wall of the column. Thiscombination eliminates the potential variability of manual alignment anddepth placement of the basket/spacer into the column and ensures aconsistent fit every time. Critical to the function of the column is thealignment of the basket/spacer openings with the column inlet in the toparm. This prevents misalignment and consequent restricted flow andpossible back pressure and also ensures consistent and timely out put ofeluent to the patient.

Another improvement is to make the column assembly out of a radiationresistant or tolerant material, such as radiation resistantpolypropylene. Likewise, the flexible tubing and Luer connector are madeof radiation resistant or tolerant materials, such as radiationresistant polyvinylchloride. Furthermore, the Luer connector on theflexible tube and its counterpart Luer connector on the column assemblyare configured to provide for a tight lock which will not leak and whichwill not loosen or inadvertently disconnect during use.

THE TECHNICAL PROBLEM AND ITS SOLUTION

The invention was designed to solve a number of technical problemsexperienced with prior art pharmaceutical containers.

1. Leakage From the Stopper/Column Interface

Leakage from the flange (or other area) of the seal of priorpharmaceutical containers such as column/stopper assembly systems wasfound to occur when the system was exposed to increasing pressure.

The new seal, consisting of a stronger material crimped at optimizedcrimping pressure, prevents leakage at the flange seal area even atincreasing pressure.

2. Ballooning

Ballooning and/or burst of rubber materials (both before and afterirradiation) through the center hole of current aluminum seals has beenobserved when they are subject to repeated pulsations of pressurecycling. The seals of the invention, which are stronger and are crimpedat optimized pressure, reduce the likelihood of this problem. However,in a preferred embodiment the seal used in the improved container of theinvention has a center hole of reduced size. For example, a seal withthe configuration of those in FIG. 5B, FIG. 5C, FIG. 5E or FIGS. 6A and6B may preferably be used. Due to the small center hole and strength ofthese seals, and crimping at optimized pressure, ballooning and/or burstof rubber materials is prevented. Consequently, pharmaceuticalcontainers of the invention, and particularly column/stopper systems ofthe invention, can be exposed to much higher pressures during use of thesystem in the field.

In addition, the larger surface area of the crimp resulting from thereduction of the diameter of the center hole serves as additionalsupport for the rubber closure and inhibits possible rupture as it isweakened over time due to the cumulative effect of exposure to radiationfrom the column or container content.

Also, the stopper is made of a radiation resistant or tolerant material.This also helps prevent ballooning and bursting.

3. Leakage Through Puncture Points

Leakage through puncture points has been observed in prior artpharmaceutical containers. Such leakage may be eliminated in containersof the invention through a combination of the stronger seal material,preferably a smaller center hole, and crimping at optimized pressure.

4. Splitting of the Seal

Splitting or tearing of current aluminum seals has been observed atpressures intended for use with a pharmaceutical container system (orpressures to which the system can potentially be exposed during intendedusage in the field).

Due to the strength of the new seal material, no splitting or rupture ofseal material is observed at pressures intended for use. For example,the seals on the columns of the invention do not split or rupture whenused in, for example, a rubidium generator at intended pressures.

5. Inconsistent Manual Crimping Procedure

The manual crimping procedure commonly used with many prior containersystems, including radioisotope column systems, is not always consistentand thus does not result in reproducible crimping pressures.Over-pressuring results in buckling and collapse of the skirt of theseal material. Under-pressuring results in a loose overseal. Use of theautomatic or semi-automatic crimping procedure of the invention withcompressed or pressurized air results in consistent/reproduciblecrimping pressures, and enables selection of optimized crimpingpressures when crimping various seal materials.

6. Maintenance of Consistent Flow/Reduction of Back Pressure

In some prior pharmaceutical columns, flow rate of the eluent throughthe column could be partially or completely blocked because the stopperblocked the outlet arm of the column. The outlet arm of the container ofthe invention has been repositioned slightly and a small piece ofplastic removed from the inside edge of the column to create a recess ornotch where the outlet arm enters the column lumen to prevent a stopperfrom blocking flow. A small reinforcement piece of resin is added to theoutside of the column between the outlet arm and column body to provideadditional strength. The recessed outlet arm and notch near the bottomof the column body greatly reduces the chance of back pressure due to astopper blocking the outlet arm.

7. Inconsistent Positioning Within Column

In a column for a radioisotope generator, a plastic basket or spacer issupplied separately and is placed on the top of the packed column beforethe seal or closure is inserted and the seal crimped into place. Inprior columns, the baskets/spacers, which hold the column packing inplace, were not easily positioned consistently both in terms of depthand orientation. In the improved columns of the invention, two smallorientation knobs have been added to the outside of the topbasket/spacer and these orientation knobs are positioned 180° apart.These knobs fit into two small slots cut into the wall of the column.This combination eliminates the potential variability of manualplacement of the basket into the column, ensuring a consistent fit fromgenerator to generator and reducing the variability in packing densityassociated with this manual process.

8. Degradation Due To Radiation

Many materials degrade when exposed to radiation. Degradation includespossible changes in color, loss of flexibility, increased brittlenessand the leaching out of various substances from the materials. To avoidthese potential problems, the column assembly, stopper, flexible tubingand Luer connectors are made out of radiation resistant or tolerantmaterials.

Frequently, when a material is said to be radiation resistant ortolerant, that means the material can withstand the amount of radiationused for sterilization, which is typically about 25 kGy. For thepurposes of the present invention, however, a material is radiationresistant or tolerant when it can be exposed to about 145 kGy radiationand not degrade to the point where the functioning of the columnassembly will be adversely affected.

9. Properly Closed Luer Locks

Luer locks are known in the art. However, it can be difficult todetermine when a Luer lock has been sufficiently tightened to form atight, non-leaking lock. Thus, one improvement is to provide for one ormore tabs on each Luer connector. When the tabs achieve a certainorientation with respect to each other, for example when the tabs lineup, such orientation means that the Luer lock has been sufficientlytightened.

Another potential difficulty with Luer locks is that they can comeloose, i.e. disconnect, during use, which has the potential of causing aleak. To overcome this potential difficulty, the Luer connectors screwtogether and are each provided with one or more tabs. As the Luerconnectors approach their fully tightened position, the tabs overlap.Further tightening causes the overlapping tabs to pass by each other,which can cause a clicking sound or sensation. When this occurs, theLuer lock is sufficiently tightened. Also, the Luer locks cannot becomeloose, e.g. unscrew, because the overlapping tabs will inhibit thisaction.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1G show the inventive column assembly from different angles andcross sections.

FIGS. 2A-2D show an alternative embodiment of the inventive assemblyfrom different angles and cross sections.

FIGS. 3A-3D show a spacer or basket used in the inventive columnassembly.

FIG. 4 shows a detailed view of the bottom of the inventive columnassembly.

FIGS. 5A-5F show various crimp seals that may be used with the inventivecolumn assembly.

FIG. 5A shows a prior art crimp seal.

FIGS. 6A and 6B show a preferred crimp seal.

FIGS. 7A-7D show a stopper for use with the inventive column assembly.

FIGS. 8A-8D show an improved Luer lock.

FIG. 9 is a diagram of the entire radionucleotide generator system.

DETAILED DESCRIPTION OF THE INVENTION

Referring now to FIG. 1, FIG. 1A shows a side view and FIG. 1B shows abottom view of the inventive container (e.g., column assembly) of oneembodiment of the invention. FIG. 1C is another side view of theinventive column assembly, cut along line A-A of FIG. 1B. FIG. 1D isdetail B from FIG. 1C, at a scale of 3:1 compared to FIG. 1C. FIG. 1E isa top view of the inventive column assembly, cut along line E-E of FIG.1A. FIG. 1F is another side view of the inventive column assembly, cutalong line C-C of FIG. 1B. FIG. 1G is detail D of FIG. 1F, at a scale of2:1 compared to FIG. 1F.

FIG. 1A has an inlet arm 1 which has an inlet arm female Luer cap 2 atits distal end. The proximal end of the inlet arm 1 attaches to theupper portion of a column 3. There is also an inlet arm support means 4to support the inlet arm 1. The support means is preferably materialwhich is added to support the inlet arm 1. Preferably, this material isthe same material used to construct the column assembly. As shown, theinlet arm support means 4 is a triangular shaped member attached to theinlet arm 1 and the column 3, although the shape of the support is notlimited to a triangle. It can be square, a bar passing from the inletarm 1 to the column 3, or any other suitable shape.

The column 3 has a top portion 5 and a bottom portion 6. The top portion5 comprises a first top portion 7 and a second top portion 8. The firsttop portion 7 is on top of and has a diameter greater then the secondtop portion 8, which is on top of and has a greater diameter than thecolumn 3.

The bottom portion 6 of the column 3 has a similar configuration. It hasa first bottom portion 9 and a second bottom portion 10. The firstbottom portion 9 sits below and has a greater diameter than the secondbottom portion 10, which sits below and has a greater diameter than thecolumn 3. Also shown is a bottom stopper 11.

An outlet arm 12 is attached to the bottom portion of the column 3. Thedistal end of the outlet arm 12 terminates in an outlet arm female Luercap 13. There is also an outlet arm support means 14 to support theoutlet arm 12. The support means is preferably material which is addedto support the outlet arm 12. Preferably, this material is the samematerial used to construct the column assembly. As shown, the outlet armsupport means 14 is a triangular shaped member which attaches to thecolumn and the outlet arm 12, although the shape of the support is notlimited to a triangle. It can be a square, a bar passing from the outletarm 12 to the column 3, or any other suitable shape.

FIG. 1C shows a cross section of the inventive column assembly, cutthrough line A-A of FIG. 1B. As shown, the inlet arm 1, column 3 andoutlet arm 12 are hollow.

Turning to the hollow interior or lumen of the column 3, it firstdefines a top stopper receptacle area 15. Below that and incommunication with it is a top basket receptacle area 16. As shown inFIG. 1C, the top basket receptacle area 16 contains a top basket orspacer 17. Following that is a packing material containing area 18.Underneath the packing material containing area 18 is a bottom screen19, followed by a bottom open area 20. Underneath the bottom open area20 is a bottom stopper receptacle area 21.

FIG. 1C shows the bottom stopper 11 inserted into the bottom stopperreceptacle area 21 of the column 3. Note that the bottom stopper 11consumes most of the bottom stopper receptacle area 21. This minimizesthe dead volume in the bottom stopper receptacle area 21. Minimizationof the dead volume minimizes mixing of fresh, radioactive eluent withnon-radioactive or decayed eluent, which could dilute the fresh eluent,thereby maintaining a narrow rubidium-82 bolus profile.

The inlet arm 1 and outlet arm 12 are each hollow, the hollow portionsbeing 22 and 23 respectively, and are in communication with the hollowportion of the column 3. As shown in FIG. 1C, the hollow portion 22 ofthe inlet arm 1 is in communication with the top basket receptacle area16.

The intersection of the column 3 and the outflow arm 12 is shown in moredetail in FIG. 1D. As shown therein, no portion of the outflow arm 12extends into the hollow portion of the column 3, as was the case withcertain prior art column assemblies. Also, the hollow portion 23 of theoutflow arm 12 intersects the hollow portion of column 3 at the top ofthe bottom stopper receptacle area 21 or at about the place the bottomstopper receptacle area 21 and the bottom open area 20 intersect. Thisconfiguration, not found in prior art column assemblies, prevents thebottom stopper 11 from blocking the outflow arm 12.

In a preferred embodiment, an outflow notch 25 is formed where thehollow portion 23 of the outflow arm 12 intersects the hollow interiorof the column 3, thus further preventing any blockage of the outflow arm12 by the bottom stopper 11. This embodiment is shown in more detail inFIG. 4.

FIG. 1E is a top view of the inventive column assembly. Visible fromthis perspective are, for example, the top basket or spacer 17 and thetop basket receptacle area 16. Also shown are notches 24 a and 24 b.

The notches 24 a and 24 b are made in the wall of the top basketreceptacle area 16. As shown in FIG. 1E, they are 180 degrees opposed toeach other. They are configured to cooperate with a pair of protrusionswhich appear on a top basket (discussed below with respect to FIGS.3A-3D) such that the protrusions fit into notches 24 a and 24 b. Thisconfiguration insures proper placement of the top basket into the topbasket receptacle area 16 so that the top basket is straight and at thecorrect depth. In prior art column assemblies, which lacked thesenotches and protrusions, it was possible to insert the top basket insuch a manner that it was not straight and/or at the wrong depth, whichadversely affected the function of the column assembly.

FIG. 1E shows two notches 24 a and 24 b 180° opposed to each other. Itis understood that the present invention is not limited to thisconfiguration. Rather, there can be 1, 3, 4, 5, 6 or more notchespresent in the wall of the top basket receptacle area 16 in anyconfiguration, so long as these notches cooperate with protrusions onthe top basket to insure its proper fit.

FIG. 1F shows a side view of the inventive column assembly, cut alongline C-C of FIG. 1B. FIG. 1G is detail D of FIG. 1E, showing analternative embodiment for the first top portion 7 a. As shown in FIG.1G, this first top portion 7 a slopes downwardly from its top, whereasthe first top portion 7 of FIG. 1F is squared off, i.e., non-sloping.

FIGS. 2A-2D show an alternative embodiment of the inventive columnassembly. As shown in FIG. 2D, which is detail B from FIG. 2C at a scaleof 3:1, the bottom stopper 11 a is configured to fit into substantiallyall of the space of the bottom stopper receptacle area 21. This insuresa better fit between the outer wall of the bottom stopper 11 a and theinner wall of the bottom stopper receptacle area 21, thus furtherinsuring against any leaks. In addition, the stopper 11 a reduces thedead volume in the bottom stopper receptacle area 21. Minimization ofthe dead volume minimizes mixing with non-radioactive or decayed eluent,which could dilute the fresh eluent, thereby maintaining a narrowrubidium-82 bolus profile. The bottom stopper 11 a further comprises abottom stopper hollow space 11 b. This bottom stopper hollow space 11 bhelps prevent the bottom stopper 11 a from blocking the outflow arm 12.

The column assembly is preferably made of polypropylene. Prior artcolumn assemblies were made with H5820 polypropylene. While that productcan still be used, in a preferred embodiment the polypropylene randomcopolymers PP P5M4R-034 or PP 13R9A (Huntsman Polymers (The Woodlands,Tex.)) can be used because they are more resistant to radiation than theprior art H5820 polypropylene. See the Prospector X5 data sheets withATSM and ISO properties for PP P5M4R-034 and PP 13R9A, which areincorporated herein by reference in their entirety. Of the two Huntsmanpolypropylenes, PP 13R9A is the more preferred, based upon UV profile,Instron stress testing and appearance after gamma-irradiation.

The manufacturing process for the inventive column assembly has alsobeen improved. A new automatic mold has been designed which increasesthe quality and appearance of the column assembly, and which increasesthe efficiency of the manufacturing process. Manufacturing is presentlydone by Duerr Molding (Union, N.J.).

For example, pins are used to form the hollow portions of the inlet arm22 and outflow arm 23. In the prior art molding process, these pins werenot fixed, so they floated. As a result, the side wall thickness of theinlet arm 1 and outlet arm 12 varied. In the present process, the pinsare fixed. Therefore, the thickness of the side walls is more uniform.

Also, as described above, the position of the outflow arm 12 has beenmoved, the outflow arm no longer protrudes into the hollow interior orlumen of the column 3, and the outflow arm resides in a recess or notch.This prevents the outflow arm from being blocked. Furthermore, supportmeans 4, 14 are provided to strengthen the inlet arm 1 and the outflowarm 12. In addition, notches 24 a and 24 b are provided for the properplacement of the top basket.

In the inventive column assembly shown in, for example, FIG. 1A and FIG.2A. The inlet arm 1 and the outlet arm 12 are straight. That is becausethis is the way the column assembly looks at the end of the moldingprocess. In use, the inlet arm 1 and the outlet arm 12 are curvedupward, in much the same configuration as the prior art CardioGen®generator is used.

Further improvement to the manufacturing process and column assembly aredescribed throughout the instant specification.

The packing material area 18 of the column 3 is designed to receivepacking material. The type of packing material used depends upon theintended use of the column arrangement.

When used as, for example, a rubidium-82 generator, such as CardioGen®,the packing material is one which will adhere strontium-82 but willallow for the elution of rubidium-82. Strontium(II)-82 decays intorubidium(I)-82. Elution of strontium-82 is not desired because it bindsto bone and exposes the patient to unnecessary radiation exposure.Presently, stannic oxide is the preferred packing material.

The packing material is loaded into the column 3 in a conventionalmanner. The column 3 is then loaded with strontium-82 in a conventionalmanner. A liquid containing the strontium-82 is slowly added to the topof the packed column and allowed to flow through it by the force ofgravity. If necessary, a small vacuum can be used. Also, the packingmaterial is preferably wetted before the strontium-82 is added. Slowaddition of the strontium-82 is preferred because it will result in thestrontium-82 being absorbed as close to the top of the column aspossible.

Filters, preferably fiberglass filters, can also be used in thisconventional loading procedure. For example, two fiberglass filters arefirst placed in the column 3, then a portion of the packing material isadded, followed by a single fiberglass filter, then the remainder of thepacking material, then two more fiberglass filters. Once filled, the topbasket or spacer 17 is inserted into the top basket receptacle area 16.The top basket 17 acts as a retainer to hold the packing material inplace.

FIGS. 3A-3D show schematics of the spacer or top basket 26 of theinventive column assembly. The spacer or top basket 26 is cylindrical inshape with an open top portion 27 and a screen 28 at the bottom portion29. Another top basket or spacer 17 of similar configuration is shown inFIGS. 1A-1G, placed in the top basket receptacle area 16.

As shown in the embodiment of FIGS. 3B and 3D, the top basket 26actually has three cylindrical areas, a top cylindrical area 30, amiddle cylindrical area 31 and a lower cylindrical area 32. The top 30and bottom 32 cylindrical areas have diameters about equal to eachother, and their diameters are greater than the diameter of the middlecylindrical area 31.

The top basket 26 also contains protrusions 33 a, 33 b which aredesigned to cooperate with notches 24 a, 24 b in the top basketreceptacle area 16. In operation, the protrusions 33 a, 33 b fit intothe notches 24 a, 24 b to insure proper alignment of the top basket 26in the top basket receptacle area 16. When so positioned, the top basket26 acts as a retainer to hold the packing material in place.

As shown in FIGS. 3A and 3C, the two protrusions 33 a, 33 b are 180°opposed to each other. They are located at the top cylindrical area 30.As was the case with the notches 24 a, 24 b, the present invention isnot limited to this configuration. Rather, there can be 1, 3, 4, 5, 6 ormore protrusions, in any orientation, so long as they cooperate with thenotches to help insure a proper fit for the top basket 26.

The top basket 26 also contains a side opening 34. As shown in FIGS. 3Band 3D, the side opening is in the middle cylindrical area 31 of the topbasket 26. The purpose of the side opening is to line up with the inletarm 1 when the top basket 26 is placed in the top basket receptacle area16. In this arrangement, when a liquid is introduced into the inlet arm1, it will pass through the side opening 34 into the top basket 26.

The top basket 26 can be made of any suitable material, such aspolypropylene. Preferably, the material will be radiation resistant,i.e. resistant to degradation in the presence of a radioactive material.More preferably, the top basket 26 is made of the same material used toconstruct the column assembly. In a preferred embodiment, that materialis PP P5M4-R-034 or PP 13R9A polypropylene (Huntsman Polymers (TheWoodlands, Tex.). Even more preferably, the material is the PP 13R9Apolypropylene. In a yet further preferred embodiment, the top basket 26is molded at the same time the rest of the column assembly is molded.

As discussed above, FIG. 4 shows a detailed view of the bottom 6 portionof the column 3. FIG. 4 shows the outflow notch 25 where the hollowportion 23 of the outflow arm 12 intersects the hollow interior of thecolumn 3. The outlet notch 25 prevents blockage of the hollow portion 23of the outflow arm 12 by the bottom stopper 11 (not shown in FIG. 4).

FIGS. 5B-5F show various types of crimp seals to use with the presentinvention. FIG. 5A shows the current, prior art crimp seal. FIGS. 5B-5Fshow various alternate embodiments of the crimp seal.

The function of the crimp seal is to form a tight, crimped seal betweenthe stoppers (described below) and the pharmaceutical container toprevent leakage. Also, a central hole is provided in the crimp seal toallow for the insertion of a needle or similar device. In one preferredembodiment the pharmaceutical container is a column, or column assembly,such as one used in a rubidium generator.

The crimp seal can be made of any material, such as plastic or metal.The material should preferably be radiation resistant, and of sufficientstrength to withstand pressures of at least 90 psi and preferably up to160 psi. More preferably, the material should be metal. Preferred metalscomprise aluminum, steel and tin, or suitable alloys or mixturesthereof. The metal can be optionally coated. For example, tin coatedsteel can be used.

The diameter of the crimp seal will vary according to use, for example,vary according to the diameter of the pharmaceutical container which isto be crimped. With respect to a column assembly to be used as arubidium-82 generator, such as CardioGen®, the diameter of the crimpseal is preferably about 20 mm across its top.

FIG. 5A shows a conventional prior art crimp seal 35. It is made out ofaluminum which is about 0.20 mm thick, has a flat top portion 36 with adiameter of about 20 mm with central hole 37 of about 9.5 mm in diameterand a skirt 38 about 7.5 mm high.

There are several potential problems with this prior art crimp seal.First, because aluminum with a thickness of only 0.20 mm is used, thecrimp seal might not be strong enough to insure a strong, leakproofseal. Second, the central hole 37 is large, and therefore the stoppermight not be properly supported. Also, the larger central hole 37 mayallow for ballooning of the stopper. Third, this crimp seal is manuallycrimped to the column 3. Manual crimping can result in undesirablevariability of crimping pressure and, accordingly, can affect how wellthe crimp seal 35 seals the column 3 to prevent leakage.

FIG. 5B shows one type of useful crimp seal 39. This crimp seal 39comprises two parts, a top crimp member 40 and a bottom washer 41. Boththe top crimp member 40 and the bottom washer 41 are made of aluminum(vendor—West). The thickness of the aluminum for each part can varydepending upon the intended use, but the aluminum used for each memberis generally about 0.20 mm thick.

The top crimp member 40 has a central hole 42 and a skirt 43. The sizeof each, and the diameter of the crimp seal, can vary depending uponuse. As shown in FIG. 5B, the central hole 42 has a diameter of about6.4 mm and the skirt 43 is about 7.6 mm high. The diameter of the topcrimp member 40 is about 20 mm. The top crimp member 40 also has a cover44, which covers the central hole 42 when not in use but can be pulledor pealed back when in use. Also, while none of FIGS. 5C through 5F orFIGS. 6A and 6B show a cover, it is understood that each of theseembodiments can employ a cover if desired.

FIG. 5B also employs a bottom washer 41. The bottom washer 41 contains acentral hole 45. The bottom washer central hole 45 can have a diametergreater than, the same as or smaller than the diameter of the centralhole 42 in the top crimp member 40. As shown in FIG. 5B, both centralholes 45, 42 have about the same diameter, i.e. about 6.4 mm. The bottomwasher 41 does not have a skirt. The diameter of the bottom washer 41 isabout 20 mm.

When used, the bottom washer 41 is placed below the top crimp member 40and both are crimped into place. Crimping is preferably performed via anautomatic or semi-automatic crimper, which is discussed in more detailbelow. In the alternative, other processes which control the crimpingpressure applied can be used.

FIG. 5C shows another embodiment of the inventive crimp seals. Thiscrimp seal 46 comprises a single member. It is made out of steel(vendor—Microliter). The thickness of the steel can vary according tothe intended use, but is generally about 0.20 mm thick. This crimp seal46 is about 20 mm in diameter, contains a central hole 47 of about 5.0mm in diameter and has a skirt 48 about 7.2 mm high. The crimp seal 46is preferably crimped into place using an automatic or semi-automaticcrimper, although other processes which control the pressure applied canbe used.

FIG. 5D shows yet another embodiment of the inventive crimp seals. Thiscrimp seal 49 comprises a single member. It is made out of steel(vendor—Microliter). The thickness of the steel can vary according tothe intended use, but is generally about 0.20 mm thick. This crimp seal49 has a diameter of about 20 mm, contains a central hole 50 of about8.0 mm in diameter and a skirt 51 about 7.2 mm high. The crimp seal 49is preferably crimped into place using a semi-automatic crimper,although other processes which control the pressure applied can be used.

FIG. 5E is yet still another embodiment of the inventive crimp seals.This embodiment comprises two parts, a top crimp member 52 and a bottomwasher 53. Both the top crimp member 52 and the bottom washer 53 aremade of aluminum (vendor—Microliter). The thickness of the aluminum canvary depending upon the intended use, but the aluminum used for eachmember is generally about 0.20 mm thick.

The top crimp member 52 has a central hole 54 and a skirt 55. Thecentral hole 54 has a diameter of about 9.6 mm and the skirt 55 is about7.6 mm high. The top crimp member 52 has a diameter of about 20 mm.

The top crimp member 52 also contains an insert 56, which is seated inor under the central hole 54. The insert 56 can be made of any suitablesubstance, but is preferable made of metal, such as steel, aluminum ortin, or plastic. The insert 56 also contains an insert central hole 57,which has a diameter of about 5 mm.

The bottom washer 53 also has a central hole 58, which has a diameter ofabout 5 mm. The bottom washer 53 is about 20 mm in diameter and it doesnot have a skirt.

When used, the bottom washer 53 is placed below the top crimp member 52and the insert 56 and then all are crimped into place. Crimping ispreferably performed using an automatic or semi-automatic crimper,although other processes which control the pressure applied can be used.

FIG. 5F shows yet another embodiment of the inventive crimp seals. LikeFIG. 5E, FIG. 5F employs two members, a top crimp member 59 and a bottomwasher 60. Both members are made of aluminum (vendor-Microliter). Whilethe thickness of the aluminum can vary with the intended use, generallyeach member is about 0.20 mm thick.

The top crimp member 59 contains a central hole 61 and a skirt 62. Thecentral hole 61 has a diameter of about 9.6 mm and the skirt 62 is about7.6 mm high. The top crimp member 59 has a diameter of about 20 mm.

The bottom washer 60 also has a central hole 63. The bottom washercentral hole 63 has a diameter of about 11.4 mm. The diameter of theentire bottom washer 60 is about 20 mm. The bottom washer 60 does nothave a skirt.

When used, the bottom washer 60 is placed below the top crimp member 59.Both are then crimped into place. Preferably, an automatic crimper isemployed, although other processes which control the pressure appliedcan be used.

FIGS. 6A and 6B show an alternate and preferred embodiment of theinventive crimp seals. This crimp seal 64 comprises a single member. Itis made out of steel (vendor—Microliter), code #20-000 M. See theMicroliter Product Catalog, which is incorporated herein by reference inits entirety. The thickness of the steel is about 0.20 mm.

The crimp seal 64 contains a central hole 65 and a skirt 66. The centralhole 65 is about 5.00 mm±0.25 mm in diameter and the skirt 66 is about7.00 mm±0.25 mm high. The entire crimp seal 64 has a diameter of about20.75 mm±0.25 mm. The crimp seal 64 is preferably crimped into placeusing an automatic or semi-automatic crimper.

FIGS. 7A-7D show an improved stopper 67 to be used with the inventivecolumn assembly. The stopper 67 is preferably made from a material whichwill form a tight seal with the column assembly. In a preferredembodiment the stopper 67 is made of a material which is also resistantto radiation.

Prior art stoppers were made of materials such as Itran-Tompkins PT-29green neoprene rubber. This material had two potential disadvantages.First, it could degrade when exposed to radiation. Second, it containedlatex, which could cause allergic reactions.

Various materials were compared to the PT-29 green neoprene used in theprior art. These materials included neoprene, isoprene, bromobutyl,chlorobutyl, nitrile, isoprene/chlorobutyl, EPDM (ethylene propylenediene monomer) and Viton. These materials were coated, uncoated,siliconized and non-siliconized.

These materials were made into column assembly stoppers and wereirradiated simulating the exposure from a 100 mCi generator over a timeperiod of 45 days (about 145 kGy). Irradiated stoppers were compared tonon-irradiated controls by integrity (pressure) testing of thecolumn/stopper assemblies. Assemblies were pressurized to determine loadpressure required to cause ballooning of rubber materials or leaks/burstat the seal closure (up to about 200 psi). In addition, for the purposeof determining potential rubber extractables and/or leechables,additional column/stopper assemblies were irradiated in the presence of0.9% saline solution. The saline solution was then scanned at 250 mm forUV absorbing extractables.

Three compositions were identified as suitable to use in stoppers: WestPharmaceutical Services (Lionville, Pa.) 4588/40 isoprene/chlorobutyl;American Stelmi (Princeton, N.J.) 6720 bromobutyl; and Helvoet-Pharma(Pennsauken, N.J.) Helvoet FM 140/0 chlorobutyl. Of these materials, themost preferred product to use is the West 4588/40 isoprene/chlorobutyl.

The stopper 67 should be configured so that it forms a tight seal withthe column assembly and minimizes the dead volume (mixing), thusmaintaining a narrow rubidium-82 bolus profile and maximizingefficiency. One preferred structure for the stopper is shown in FIGS.7A-7D.

Referring to FIG. 7B, the stopper 67 comprises a generally cylindricaltop section 68 and a generally cylindrical bottom section 69. Thediameter of the stopper bottom section 69 is about the same as orslightly larger than the inside diameter of the first top portion 7 andfirst bottom portion 9 of the cylinder 3, assuming both of theseportions 7, 9 have the same diameter. If these portions have differentdiameters, then the cylindrical bottom section 69 of the stopper 67 willhave about the same or slightly larger inside diameter as the portion 7,9 it is intended to be inserted into. The reason for this configurationis to insure a tight fit between the stopper 67 and the first top 7 andfirst bottom 9 portions of the cylinder 3. A tight cylinder 3/stopper 67interface helps prevent leakage.

The stopper top section 68 has a greater diameter than the stopperbottom section 69 to prevent the stopper 67 from being inserted too farinto the cylinder 3. In addition, optionally the stopper top section 68can have a curved upper edge 70.

The stopper bottom section 69, in one preferred embodiment, contains aU-shaped groove 71 in its base. See FIG. 7A. The U-shaped groove 71traverses greater than half the length of the stopper bottom section 69,and it terminates in a semi-circular section 72. Preferably, the centerpoint 73 of the semicircular section 72 should be about at the centerpoint of the stopper bottom section 69.

The stopper top section 68 contains a central circular indentation 74 inits top surface. See FIG. 7C. Preferably, the diameter of the centralcircular indentation 74 has a diameter about equal to the width of theU-shape groove 71. As shown in FIGS. 7B and 7D, the central circularindentation 74 and the U-shaped groove 71 should preferably line up witheach other when the stopper is viewed through its cross-section. Thecentral circular indentation 74 and U-shaped groove 71 allow for easyinsertion of a needle or similar device into the stopper 67.

The surface of the stopper top section 68 also contains three sphericaldots 75 a, 75 b, 75 c and an indicia, such as a spherical lug 76. Theyare spaced equidistant from each other around the central circularindentation 74. Also, the spherical lug 76 is placed so that it is abovethe U-shaped grove 71. In this configuration, when the stopper 67 isinserted into the first top portion 7 of the column 3, the spherical lug76 can be lined up with the inlet arm 1. Thus, the open end of theU-shaped groove 71 will face the inlet arm 1, thus preventing itsblockage.

The same holds true for the first bottom portion 9 of the column 3. Whenthe stopper 67 (stopper 11 shown in FIGS. 1A-1G and stopper 11 b inFIGS. 2A-2D can have the same or different configurations from stopper67) is inserted therein, the spherical lug 76 is lined up with theoutlet arm 12. The open end of the U-shaped groove 71 will then face theoutlet arm 12 and prevent its blockage.

It is understood that the present invention is not limited to a U-shapedgroove 71. Any other configuration, such as a notch, can be used so longas any potential blockage is avoided. In fact, if there is no potentialfor blockage, the U-shaped groove 71 or alternative structure can beeliminated.

The stopper 67 is affixed to the column 3 via crimping, using thecrimping seals described above in FIGS. 5 and 6. In the prior art,crimping was performed manually. The disadvantage of manual crimping isthat it is not always uniform. One problem this can cause is leakage. Toovercome this potential problem, the present invention preferably usesautomatic or semi-automatic crimping.

Any automatic or semi-automatic crimper can be used for the presentinvention, so long as it can consistently crimp seals at a specified,controlled pressure. One preferred type of automatic crimper is apneumatic crimper, which is powered by gas. One example of a pneumaticcrimper suitable for the present invention as an AP/CP2000 LightweightAir Crimper/Decapper (Laboratory Precision Limited, UK). See LaboratoryPrecision Limited brochure copyrighted Apr. 4, 2001, which isincorporated herein by reference in its entirety.

In the crimping process, a stopper 67 is inserted into the top portion 5or bottom portion 6 of the column 3, so that it is seated in the firsttop portion 7 or first bottom portion 9, respectively. A crimp seal or acrimp seal and washer (see FIGS. 5 and 6) is/are placed over the stopper67. The crimp seal or crimp seal and washer are then crimped into place,either manually or, preferably, automatically or semi-automatically.While the crimping pressure used is optimized based upon theconfiguration and material of the crimp seal and stopper, generallyabout 117±3 psi pressure is used.

The resulting crimped crimp seal/stopper configuration can withstand theoperative pressures of the system, i.e. at least 90 psi and preferablyup to 200 psi.

When in operation, connector tubes (not shown) are connected to thecolumn assembly. Referring to FIG. 1A, both the inlet arm 1 and theoutlet arm 12 have a female Luer cap 2, 13 at their distal ends. Thesefemale Luer caps 2, 13 engage male Luer caps at the proximal ends of theconnector tubes.

Prior art connector tubes can discolor from clear to brown and hardenupon prolonged exposure to radiation. Also, the Luer connector candiscolor and become brittle. In addition, the Luer connectors can loosenor become unintentionally disconnected during use.

Accordingly, the present invention includes constructing connectortubing out of radiation resistant materials. Preferably, the tubing ismade from a flexible radiation resistant polyvinyl chloride (PVC) andthe Luer connector is made from a rigid radiation resistant PVC. Forexample, a preferred material for constructing the tubing is AlphaGaryPVC 2232 A/R-78S Clear 030X. See AlphaGary Test Result Certificate,Report Date Aug. 20, 1999; Technical Data, Date of Origin 8/99; andMaterial Safety Data Sheet printed Apr. 5, 2000; which are incorporatedherein by reference in their entirety. A preferred material forconstructing the Luer connector is AlphaGary PVC 2212 RHT/1-118 Clear080X. See AlphaGary Data Sheet, Revision Date 4/02, which isincorporated herein by reference in its entirety. Also, using thisAlphaGary rigid PVC for the Luer connector allows the heat bonding oftubing to the Luer connector.

In an alternative embodiment of the present invention, the distal end ofthe connector tube attached to the outlet arm 12 of the column assemblyas shown in FIG. 1A has a check valve (not shown) attached to it. In apreferred embodiment, the check valve is included in the patient tube103, shown in FIG. 9, either before or after the patient sterilizationfilter 104. The check valve prevents a back flow of fluids from enteringthe connector tube when connected to or disconnected from a patient.

In another alternative embodiment, sometimes the generator is placed sofar away from a patient that the patient tube cannot reach all the wayto the patient. In this instance, one or more extension tubes can beadded, the length of which is sufficient to reach the patient.Preferably, a single extension tube is used and in a preferredembodiment, it is made of the same materials as the connector tubesdiscussed above to provide for, e.g., flexibility and radiationresistance.

The present invention further includes an improved Luer lock. Theimprovements are described below. An embodiment of this improved Luerlock is set forth in FIGS. 8A-8D. These improved Luer locks can be usedwith the pharmaceutical containers of the present invention, or in anyother indication where it is desirable to have a connection that willnot loosen or inadvertently disconnect.

In the embodiment of FIGS. 8A-8D, FIG. 8A show a side view of theinventive column assembly with the inlet arm 1 projecting forward. Alsoshown is the female Luer cap 2 at the distal end of the inlet arm 1.

As shown in FIG. 8C, the female Luer cap 2 terminates in a flange 77.The flange 77 can be flat or, as shown, contain a groove 78. Otherconfigurations, known in the art, can also be used.

The flange 77 is configured to engage and mate with threads 78 in a maleLuer cap 79. When the two caps 2, 79 are screwed together, they form atight Luer lock which will be leak resistant. This configuration isshown in FIG. 8D.

One difficulty with a Luer lock is to know when the male and female caps79, 2 have been connected sufficiently to form a tight lock. To overcomethis problem, one or more tabs are provided on each of the male 79 andfemale Luer caps 2. As shown for example in FIGS. 8C and 8D, two tabsare provided on each cap 80 a, 80 b, 81 a and 81 b, although it isunderstood that the invention is not limited to this configuration only.For example, each of the Luer caps can also contain 1, 3, 4, 5, 6 ormore tabs.

In one embodiment, the female Luer cap tabs 80 a, 80 b and the male Luercap tabs 81 a, 81 b are so positioned that when the Luer locks issufficiently tight, the tabs line up with each other. This way, a userknows when tightening is completed. The present invention, however, isnot limited to this one configuration, so long as the tab or tabs oneach of the Luer connectors 79, 2 are arranged in a desiredconfiguration to demonstrate that the Luer connectors 79, 2 aresufficiently tightened. In another preferred embodiment, as shown inFIG. 8D, the male Luer cap tabs 81 a, 81 b overlap with the female Luercap tabs 80 a, 80 b. The tabs are so positioned that this overlap occurswhen the tightening is complete. At the point of desired tightening, thetabs 80 a, 80 b, 81 a, 81 b pass by or click past each other. That way,the Luer locks cannot be over- or under-tightened. Also, loosening ordisconnection of the Luer lock during use is prevented by theoverlapping of the tabs, preventing the Luer connectors 79, 2 fromturning in a loosening direction.

Although the inventive Luer locks are shown only as part of thegenerator as shown in FIGS. 8A and 8B, the inventive Luer locks can beused in place of conventional Luer locks at any place in the inventivegenerator system. Moreover, the inventive generator system can contain acombination of conventional Luer locks and the inventive Luer locks.Finally, the inventive Luer locks are not solely intended for use withthe inventive generator system. Rather, they can be used in place ofconventional Luer locks wherever those conventional Luer locks are used.

When the inventive column assembly is used as, for example, arubidium-82 generator, it is pre-packaged with strontium-82 in thefactory. That is, the product shipped to the customer is radioactive.Therefore, the radioactive column assembly is shipped in a shielded(e.g. lead) container.

Nevertheless, leakage is still a concern upon shipping. Thus, to improvesafety when the radioactive column assembly is shipped, an inventiveimprovement is to ship the product with a liquid absorbent pad.Preferably, the shipping pad is a GP100 absorbent pad (Shell PackagingCorporation, Springfield, N.J.). GP100 is a 100% polypropylene non-wovenmat of randomly oriented micro-fibers (2-10 micron diameters). See SPCGeneral Product Specifications for GP100 dated May 26, 2003, which isincorporated herein by reference in its entirety. This type of shippingpad is useful in absorbing any leaks which may occur.

SUMMARY OF THE PREFERRED EMBODIMENTS

Improved Seal

The new seal, which is used to crimp the rubber stopper in place in apharmaceutical container and particularly, which is used to seal aradioisotope generator column/stopper assembly system, such asCardioGen®, is preferably made of a sufficiently strong material toeliminate the problems discussed above. FIGS. 5B through 5F and FIGS. 6Aand 6B illustrate various method of reinforcing the top portion of theseal by use of a second layer (washer) or use of a stronger materialsuch as steel/tin in addition to reducing the size of the center hole.The material may include metal or plastic, but is preferably metal. Themetal may include heavy gauge aluminum, steel or tin, but is preferablysteel or tin. The seal generally has the configuration shown in FIGS. 5Bthrough 5F and FIGS. 6A and 6B and may have a small or large centralhole, a shorter or longer skirt and optionally, a cover (e.g., plasticor aluminum over the central hole). The dimensions of the seal willvary, and one skilled in the art will understand that they should beappropriate to the container which is being sealed. Approximatedimensions for seals for a radioisotope generator column are shown inthe various examples in FIGS. 5B through 5F and in FIGS. 6A and 6B.These dimensions are approximate and are not intended to be limiting.

The central hole of the seals of the invention may vary in size. In apreferred embodiment the seal has a smaller central hole such as, forexample, those proportional to the central holes shown in FIG. 5B, FIG.5C, FIG. 5E and FIGS. 6A and 6B.

In one embodiment, seals of FIG. 5B through FIG. 5F and FIGS. 6A and 6Bare used to seal a radioisotope generator column. These seals areavailable from the vendors West Pharmaceutical Services (Lionville, Pa.)and Microliter Analytical Supplies Inc. (Suwannee, Ga.). In aparticularly preferred embodiment, the central hole of the seal isreduced in size such as in the seals in FIG. 5B, FIG. 5C, FIG. 5E andFIGS. 6A and 6B. The preferred configuration for this application is a1-piece steel/tin crimp with a center hole of approximately 4-5 mmdiameter and a skirt length of approximately 7.2 to 7.5 mm as shown inFIGS. 6A and 6B.

The combination of using a stronger material such as steel/tin orheavier gauge aluminum and reduction of the center hole results inoptimum performance in maintaining a secure leakage free seal under highpressure and particularly repeated exposure (pulsing or cycling) to highpressure as occurs with the use of the rubidium-82 generator as theenlarged surface area of the crimp limits excessive expansion of therubber closure under pressure.

The use of a stronger material such as steel/tin or heavy gauge aluminumfurther improves the performance of the crimp by reducing the likelihoodof failure due to relaxation or fatigue of the seal flange which isformed at the point where the crimp skirt is folded under the column orcontainer flange when exposed to high or pulsating pressures. It isunderstood that the skirt length can be varied to provide a proper fitwith the container/rubber seal combination to which it is applied.

Automatic Crimper and Improved Crimping Process

In a preferred embodiment, an automatic or semi-automatic crimper isused to crimp the seals of the invention. The automatic orsemi-automatic crimper is set at an optimized pressure and is able tocrimp seals of any material during assembly of a pharmaceuticalcontainer such as a radioisotope generator column/stopper assemblysystem. Suitable automatic crimpers include pressurized and/orcompressed air crimpers such as those available from LaboratoryPrecision Limited under the trade name/model number AP/CP2000. Use ofthe automatic or semi-automatic crimping procedure of the invention withcompressed or pressurized air results in consistent/reproduciblecrimping pressures, and enables selection of optimized crimpingpressures when crimping various seal materials.

Use of optimized pressures improves the performance of the seals of theinvention and also improves performance of seals of only moderatestrength, such as lighter gauge aluminum and some plastics.

The automatic or semi-automatic, pneumatically powered crimper used toapply the seal is preferably operated at an optimized pressure ofbetween 60-140 psi. However, although automatic or semi-automaticcrimpers are preferred, it should be noted that application of the sealis not limited to automated equipment, and systems ranging from manualto fully automatic may be used, provided their operation can beoptimized to produce repeatable and consistent predetermined pressuresin applying the seals.

Column Design Improvements

Manufacturing Process To create the new column design, a new automaticmold has been designed. The mold and the new columns produced thereinexhibit improved column quality and appearance. The new mold alsoincreases the efficiency of the manufacturing process. The increasedspeed of the new automated mold enables one operator to run the processefficiently.

Column Design The improved pharmaceutical container also includesimprovements to the design which ensure specified flow of eluent throughthe container and improve its packing and consistency. In one embodimentthe improved container comprises a column used in a radioisotopegenerator. The improved column includes a repositioned outlet arm, andthe column outlet resides in a recess or notch in the inside ledge ofthe column where the outlet arm enters the column lumen, to prevent astopper from blocking the flow. These improvements further includeintroducing small reinforcement pieces of resin to the outside of thecolumn between the outlet arm and column body and between the inlet armand column body to provide additional strength. Additionally, the seamof the inlet and outlet arms has been eliminated by changing the moldrunners. This change has improved the consistency of the inlet andoutlet arm diameters and made the arms stronger.

Furthermore, to address consistency of packing of the containers, twosmall alignment slots have been cut into the wall of the column toreceive the orientation knobs on the baskets that properly align andseat the basket in the column and limit the insertion depth into thecolumn. This improves the consistency of packing density and eliminatespotential blockage of the inlet arm. Additionally, in one embodiment,the improved column has stopper flanges and Luer flanges with muchsmoother surfaces with sharper edges to improve the sealing ability ofthe crimp. These attributes improve stopper and Luer contact to thecolumn and greatly reduce the chance of leakage. Also, the flashing onthe column is reduced greatly to enhance the appearance of the part.

Finally, the column assembly is made from a radiation resistant ortolerant material. The most preferred material is Huntsman PP 13R9Apolypropylene.

Luer Lock and Connector Tube Improvements

The Luer locks and connector tubes used with the column have also beenimproved. First, the connector tubes are made from a radiation resistantor tolerant material. Preferably, this material is AlphaGary PVC 2232A/R-78S clear 030X.

Second, the terminal end of the connector tube which attaches to thecolumn contains a male Luer cap. This male Luer cap is made of aradiation resistant material, preferably AlphaGary PVC 2212RHT/1-118clear 080X.

Third, the male and female Luer caps screw together and each containstabs, preferably two tabs each. When the tabs line up with each other inone embodiment or overlap with each other in another embodiment, thatindicates that the two Luer caps are sufficiently tightened or screwedtogether to form a tight seal or lock. Also, in a preferred embodimentthe overlapping tabs prevent the Luer caps from becoming loose, i.e.unscrewing.

FIG. 9 is a diagram of the entire radionucleotide generator system. Inthis system, a saline supply 83 is connected to a saline supply tube 84.The saline tube 84 passes through a first check valve 85 and a secondcheck valve 86. The check valves 85, 86 are used to insure that thesaline solution only flows in the direction of the rubidium generatorcolumn 3. Interspersed between the check valves 85, 86 is a syringe pump87. The syringe pump 87 connects to saline supply tube 84 at aT-junction 88 via a syringe pump luer connection 89.

After the second check valve 86, a pressure transducer 90 is connectedto the saline supply tube 84 via a pressure transducer luer connection91. The saline supply tube 84 terminates at a first sterilization filter92 and is connected to it via a first sterilization filter luerconnection 93.

The sterilization filter 92 is connected to a column connector tube 94via a column connection tube luer connector 93. The column connectortube 94 passes through a generator shield 95 and connects to the femaleluer cap 2 of the inlet arm 1 via a male luer cap as shown in FIG. 8D.The generator shield 95 prevents exposure to radiation from the column 3which can contain radioactive materials, such as strontium andrubidium-82. The inlet arm 1 is connected to the column 3 which isconnected to the outlet arm 12 as shown in, for example, FIGS. 1 and 2.The female luer cap 13 of the outflow arm 12 connects to the male luercap (not shown) of outlet connecting tube 96.

The outflow connecting tube 96 passes through the generator shield 95and connects via an outflow connecting tube luer connector 97 to adivergence valve tube 98. The divergence valve tube 98 passes through apositron (beta) detector 99, which is used to insure that the liquid tobe injected into a patient has the correct level of radioactivity.Recall that at this point the liquid, which is usually a saline solutionand starts at the saline supply 83, has now passed through the column 3and thus, will contain rubidium-82.

After the positron (beta) detector 99, the divergence valve tube 98passes to a divergence valve 100. The divergence valve 100 will divertthe liquid to either the diversion outlet tubing 101 or a wasteconnection tube 102. The diversion outlet tubing 101 connects via thepatient tube-luer connection 102 to a patient tube 103, which terminatesat a patient sterilization filter 104 which is solvent bonded at thetime of manufacture to the patient tube 103. A needle may be attached tothe patient sterilization filter 104.

The patient tube 103 can pass directly to a patient (via the patientsterilization filter 104). In an alternative embodiment, the patienttube 103 can include a check valve prior to the patient sterilizationfilter 104. The check valve may be solvent bonded at the time ofmanufacture of the assembly (not shown). The check valve can beconnected to the patient tube 103 by a check valve luer connection (notshown) which may be solvent bonded at the time of manufacture of thepatient line. In yet another alternative embodiment, the check valve canbe connected after the patient sterilization filter 104, optionally viaa luer connection. Also, as described above, if the distance to thepatient is too great, one or more additional connector tubes (alsocalled extension tubes) (not shown) can be added to the assembly tobridge the distance to the patient. For example, one or more extensiontubes may be connected with a luer fitting between the patient tube luerconnection 102 and the patient tubing 103.

The waste connector tube 109 passes through a waste sterilization filter105 to a waste bottle 106, and these can be connected to each other viaa waste luer connection 107. The waste bottle 106 is surrounded by awaste shield 108 to prevent exposure to radiation.

The system shown in FIG. 9 and discussed above contains a number of luerconnections. Some or all of these luer connections can be the inventiveluer connections described above. Conversely, some or all of the luerconnections can be of the conventional type, or do not even have to beluer connections at all, but rather can be any type of connectors, andcan be jointly referred to as “connecting means”. Preferably, some orall of the connecting means are of the inventive type while theremainder are conventional luer connections.

In addition, the tubes and connecting means are preferably made ofradiation resistant materials. Preferably, they are made of thematerials discussed above. This is especially true of those tubes andconnecting means which are exposed to radiation.

Shipping Improvements

The columns can be shipped pre-loaded with, for example, strontium-82.Therefore, the columns are shipped in sealed containers containingGP-100 absorbent material to absorb any leakage.

The above description is to be taken as illustrative and not in thelimiting sense. Many modifications can be made to the design withoutdeviating from the scope thereof.

1. An improved rubidium-82 generator comprising: a. a hollow column witha top portion, a middle portion and a bottom portion, said top portionincluding one or more notches, and a screen separating the middleportion and the bottom portion; b. a top basket with one or moreprotrusions, said one or more protrusions configured to cooperate withthe one or more notches in the top portion of the hollow column so as tocause the proper seating of the top basket in the top portion of thehollow column, said top basket further comprising a screen at its baseand a side opening; c. an inlet arm which intersects the hollow columnat its top portion at a point where the inlet arm is aligned with theside opening in the top basket, and further wherein the inlet arm has afemale Luer cap at its distal end, said female Luer cap containing oneor more tabs on its outer surface; d. an outlet arm which intersects butdoes not protrude into the hollow column at its bottom portion, whereina notch is provided at the point of intersection on the bottom portion'sinner surface, and further wherein the outlet arm has a female Luer capat its distal end, said female Luer cap containing one or more tabs onits outer surface; e. support means to support the inlet arm and theoutlet arm to the hollow column; wherein said hollow column, top basket,inlet arm, outlet arm and support means are constructed of a radiationresistant polypropylene; f. a packing material comprising stannic oxidewith strontium-82 adhered thereto, said packing material placed in themiddle portion of the hollow column above the bottom screen and belowthe screen of the top basket; g. a top stopper comprising a radiationresistant material, said top stopper configured to form a tight sealwith the top portion of the hollow column but which does not block theinlet arm; h. a bottom stopper comprising a radiation resistantmaterial, said bottom stopper configured to form a tight seal with thebottom portion of the hollow column and minimizing a dead space in thebottom portion of the hollow column, without blocking the outlet arm; i.a first crimp seal to crimp the top stopper to the top portion of thehollow column and a second crimp seal to crimp the bottom stopper to thebottom portion of the hollow column, wherein each crimp seal comprisessteel with a thickness of about 0.2 mm and a central hole about 5.0 mmin diameter, wherein each crimp seal is crimped to a pressure of about117 psi; j. a first flexible tube comprising a flexible, radiationresistant polyvinyl chloride with a first male Luer cap comprising arigid, radiation resistant polyvinyl chloride at one end of said firstflexible tube, said first male Luer cap being configured to cooperatewith the female Luer cap at the distal end of the inlet arm, so that thefirst male Luer cap and the female Luer cap at the distal end of theinlet arm can be screwed together to form a tight Luer lock, and whereinsaid first male Luer cap contains one or more tabs on its outer surfacewhich will align with the one or more tabs on the outer surface of thefemale Luer cap at the distal end of the inlet arm, when the two Luercaps are screwed together, so as to achieve a desired configuration,with respect to each other, when the Luer caps are tightened together;and k. a second flexible tube comprising a flexible, radiation resistantpolyvinyl chloride with a second male Luer cap comprising a rigid,radiation resistant polyvinyl chloride at one end of said secondflexible tube, said second male Luer cap being configured to cooperatewith the female Luer cap at the distal end of the outlet arm, so thatthe second male Luer cap and the female Luer cap at the distal end ofthe outlet arm can be screwed together to form a tight Luer lock, andwherein said second male Luer cap contains one or more tabs which willalign with the one or more tabs on the outer surface of the female Luercap at the distal end of the outlet arm, when the two Luer caps arescrewed together, so as to achieve a desired configuration, with respectto each other, when the Luer caps are tightened together.
 2. An improvedrubidium-82 generator comprising: a. a hollow column with a top portion,a middle portion and a bottom portion, said top portion including one ormore notches, and a screen separating the middle portion and the bottomportion; b. a top basket with one or more protrusions, said one or moreprotrusions configured to cooperate with the one or more notches in thetop portion of the hollow column so as to cause the proper seating ofthe top basket in the top portion of the hollow column, said top basketfurther comprising a screen at its base and a side opening; c. an inletarm which intersects the hollow column at its top portion at a pointwhere the inlet arm is aligned with the side opening in the top basket,and further wherein the inlet arm has a female Luer cap at its distalend, said female Luer cap containing one or more tabs on its outersurface; d. an outlet arm which intersects but does not protrude intothe hollow column at its bottom portion, wherein a notch is provided atthe point of intersection on the bottom portion's inner surface, andfurther wherein the outlet arm has a female Luer cap at its distal end,said female Luer cap containing one or more tabs on its outer surface;e. support means to support the inlet arm and the outlet arm to thehollow column; wherein said hollow column, top basket, inlet arm, outletarm and support means are constructed of a radiation resistantpolypropylene; f. a packing material comprising stannic oxide withstrontium-82 adhered thereto, said packing material placed in the middleportion of the hollow column above the bottom screen and below thescreen of the top basket; g. a top stopper comprising a radiationresistant material, said top stopper configured to form a tight sealwith the top portion of the hollow column but which does not block theinlet arm; h. a bottom stopper comprising a radiation resistantmaterial, said bottom stopper configured to form a tight seal with thebottom portion of the hollow column and minimizing a dead space in thebottom portion of the hollow column, without blocking the outlet arm; i.a first crimp seal to crimp the top stopper to the top portion of thehollow column and a second crimp seal to crimp the bottom stopper to thebottom portion of the hollow column, wherein each crimp seal comprisessteel with a thickness of about 0.2 mm and a central hole about 5.0 mmin diameter, wherein each crimp seal is crimped to a pressure of about117 psi; j. a first flexible tube comprising a flexible, radiationresistant polyvinyl chloride with a first male Luer cap comprising arigid, radiation resistant polyvinyl chloride at one end of said firstflexible tube, said first male Luer cap being configured to cooperatewith the female Luer cap at the distal end of the inlet arm so that thefirst male Luer cap and the female Luer cap at the distal end of theinlet arm can be screwed together to form a tight Luer lock, and whereinsaid first male Luer cap contains one or more tabs on its outer surfacewhich will overlap with the one or more tabs on the outer surface of thefemale Luer cap at the distal end of the inlet arm, when the two Luercaps are screwed together, the tabs overlapping, having been pushed pasteach other, to form a tight Luer lock which is resistant to inadvertentloosening; and k. a second flexible tube comprising a flexible,radiation resistant polyvinyl chloride with a second male Luer capcomprising a rigid, radiation resistant polyvinyl chloride at one end ofsaid second flexible tube, said second male Luer cap being configured tocooperate with the female Luer cap at the distal end of the outlet armso that the second male Luer cap and the female Luer cap at the distalend of the outlet arm can be screwed together to form a tight Luer lock,and wherein said second male Luer cap contains one or more tabs whichwill overlap with the one or more tabs on the female Luer cap at thedistal end of the outlet arm, when the two Luer caps are screwedtogether, the tabs overlapping, having been pushed past each other, toform a tight Luer lock which is resistant to inadvertent loosening. 3.An improved rubidium-82 generator system comprising: a. a rubidium-82generator including an inlet arm and an outlet arm, and being surroundedby a generator shield; b. a saline supply connected to the inlet arm ofthe rubidium-82 generator by one or more saline supply tubes connectedto each other in series, said saline supply tubes being connected toeach other and to the inlet arm of the rubidium-82, generator by a firstconnecting means; c. one or more outflow tubes connected in series andconnected to each other and to the outlet arm of the rubidium-82generator via a second connecting means; d. a divergence means at aterminal end of the outflow tubes, the divergence means being connectedto a patient tube and a waste tube such that a liquid flowing throughthe divergence means can be diverted to the patient tube or the wastetube; and e. a waste bottle surrounded by a waste bottle shield, whereinthe waste bottle is connected to the waste tube via a third connectingmeans; wherein the improvements comprise: f. support means to supportthe inlet arm and the outlet arm of the rubidium-82 generator; and g.the outlet arm intersects but does not protrude into a hollow column ofthe rubidium-82 generator at a bottom portion thereof, and a notch isprovided in the hollow column at a point of intersection of the outletarm and the hollow column.
 4. The improved rubidium-82 generator systemof claim 3, further comprising one or more additional tubes connected toeach other in series and connected between the divergence means and thepatient tube by a fourth connecting means, to provide for a desireddistance from the rubidium-82 generator to a patient.
 5. The improvedrubidium-82 generator of claim 3, wherein each of the connecting meansis a Luer connector.
 6. The improved rubidium-82 generator system ofclaim 5, wherein the Luer connector comprises a female Luer cap and amale Luer cap, wherein one of said Luer caps contains a flange and theother of said Luer caps contains threads, configured so that the flangeand threads cooperate with each other in such a way that the female Luercap and male Luer cap can be screwed together, and wherein one or moretabs are provided on each of the male and female Luer caps, the tabs onthe male Luer cap and the tabs on the female Luer cap achieving adesired configuration, with respect to each other, when the two Luercaps are tightened together.
 7. The improved rubidium-82 generatorsystem of claim 6, wherein the one or more tabs of each of the male andfemale Luer caps each comprise two tabs.
 8. The improved rubidium-82generator system of claim 6, wherein the desired configuration compriseseach of the one or more tabs on the male Luer cap lining up with acorresponding tab of the one or more tabs on the female Luer cap.
 9. Theimproved rubidium-82 generator of system of claim 6, wherein the desiredconfiguration comprises each of the one or more tabs on the male Luercap overlapping with a corresponding tab of the one or more tabs on thefemale Luer cap, thereby preventing over tightening or inadvertentloosening of the Luer lock.
 10. The improved rubidium-82 generatorsystem of claim 3, wherein the rubidium-82 generator, tubes, connectingmeans, divergence means and waste bottle are all constructed ofradiation resistant materials.
 11. The improved rubidium-82 generatorsystem of claim 3, wherein the patient tube terminates in a check valveto prevent air from entering the patient tube when the patient tube isdisconnected from the patient.
 12. The improved rubidium-82 generatorsystem of claim 11, wherein the check valve is constructed of radiationresistant materials.
 13. The improved rubidium-82 generator system ofclaim 11, wherein the patient tube includes a sterile filter and thecheck valve is attached before the sterile filter.
 14. The improvedrubidium-82 generator system of claim 11, wherein the patient tubeincludes a sterile filter and the check valve is attached after thesterile filter.